This application is to continue the University of Colorado Alcohol Research Center. This center has been in formal existence since the NIAAA Centers program was initiated in 1977. The overall goal of this Center is to define the mechanisms (genetic and functional) that determine initial sensitivity to alcohol intoxication and the development of tolerance to these effects. The Center has evolved from animal model development and characterization to the level of specific gene identification. We will utilize existing models for genetic sensitivity and develop new ones for tolerance to ethanol. Center investigators will continue to use the technique of selective breeding for specific behaviors but will also emphasize new models based on genotypic selection (congenic lines) and changes in single genes (transgenic and null mutant mice). There are proposals to isolate and identify specific genes within QTLs for initial sensitivity. We will continue to provide our unique animal models to investigators at other institutions around the world. These genetic models will be used to define the biochemical and electrophysiological mechanisms responsible for the selected behavior and to provide information about candidate genes that may be responsible for these functional changes. In addition, molecular genetic approaches will be used to elucidate differences in gene sequences responsible for behavioral, biochemical, and electrophysiological differences identified by QTL analysis. This multidisciplinary approach provides extensive interaction and synergism between projects. This goals will be accomplished by six research components, an animal production core, and administrative core, and four pilot projects.